title: The C3435T polymorphism in ABCB1 influences atorvastatin efficacy and muscle symptoms in a high-risk vascular cohort.
abstract: OBJECTIVE
  The CC genotype of the C3435T polymorphism in ABCB1 is associated with increased P-glycoprotein expression, reduced low-density lipoprotein cholesterol (LDL-C) response to atorvastatin, and a reduced area-under-the-curve in pharmacokinetic studies. We sought to assess the relationship between 1) genotype and Atorvastatin efficacy, independently of variation in cholesterol metabolism and 2) genotype and myalgia.
  
  
  METHODS
  High-risk vascular patients were genotyped and treated with atorvastatin 80 mg for 6 weeks. The lipid panel and percent LDL-C reduction with atorvastatin were related to C3435T genotype. Genotypes and allele frequency were assessed in patients with and without myalgia.
  
  
  RESULTS
  A total of 117 patients were recruited and genotyped. Of these, 98 completed the study with adequate atorvastatin adherence, and 10 reported myalgia. T and C allele frequencies were 0.63 and 0.37, respectively. A 6-week course of atorvastatin (80 mg/day) reduced LDL-C by 58% ± 11% (mean ± SD). Patients with the CC genotype showed less LDL-C reduction with atorvastatin compared with the TT/TC genotype (53% vs 59%, respectively, P = .034), and this finding was independent of variation in cholesterol metabolism (P = .045 after correction for desmosterol and cholestanol/cholesterol ratio). The T allele was more frequent in patients with myalgia than those without (0.80 vs 0.62) and the C allele less frequent (0.20 vs 0.38, P = .043).
  
  
  CONCLUSIONS
  In patients treated with atorvastatin, the CC genotype at the C3435T polymorphism in ABCB1 is associated with reduced atorvastatin efficacy independently of cholesterol metabolism. The T allele is more frequent and the C allele less frequent in patients with myalgia.
authors.affiliation: Royal Brisbane and Women's Hospital, University of Queensland Centre for Clinical Research, Building 71, Herston Qld 4029, Australia. drmhoenig@yahoo.com.au
authors.forename: Michel R
authors.initials: MR
authors.lastname: Hoenig
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Walker
authors.forename: Christine
authors.initials: C
authors.lastname: Gurnsey
authors.forename: Karen
authors.initials: K
authors.lastname: Beadle
authors.forename: Leslie
authors.initials: L
authors.lastname: Johnson
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000368:Aged; D000069059:Atorvastatin; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006538:Heptanoic Acids / Q000009:adverse effects* / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D009135:Muscular Diseases / Q000139:chemically induced* / Q000235:genetics; D010146:Pain / Q000139:chemically induced* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011758:Pyrroles / Q000009:adverse effects* / Q000494:pharmacology* / Q000627:therapeutic use; D012306:Risk; D014652:Vascular Diseases / Q000188:drug therapy* / Q000235:genetics
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D006538:Heptanoic Acids; D011758:Pyrroles; D000069059:Atorvastatin